Cancer is a class of diseases that affects people world-wide. Generally, cells in a benign tumor retain their differentiated features and do not divide in a completely uncontrolled manner. A benign tumor is usually localised and non-metastatic.
In a malignant tumor, cells become undifferentiated, do not respond to the body's growth control signals, and multiply in an uncontrolled manner. Malignant tumors are generally divided into two categories: primary and secondary. Primary tumors arise directly from the tissue in which they are found. Secondary tumors may be originated from the primary tumors or may be originated elsewhere in the body, and are capable of spreading to distant sites (metastasizing) or metastasis. The common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems or blood streams.
Tumor metastases are the major cause of mortality in cancer patients. There is compelling evidence that angiogenesis is clinically relevant to the progression and metastasis of cancer. Angiogenesis consists of several steps: the basement membrane degradation, endothelial cell proliferation and migration, and capillary tubule formation. New capillary vessels recruited by tumors deliver nutrients and oxygen into a growing tumor, and remove catabolites and carbon dioxide. Diseases associated with abnormal angiogenesis require or induce vascular growth. For example, corneal angiogenesis involves three phases: a pre-vascular latent period, active neovascularization, and vascular maturation and regression. The identity and mechanism of various angiogenic factors, including elements of the inflammatory response, such as leukocytes, platelets, cytokines, and eicosanoids, or unidentified plasma constituents have yet to be revealed.
This activity is also required for metastasis. One of the important early events in the development of the metastatic phenotype is the induction of genes involved in angiogenesis such as VEGF and other proteins which are released from tumor cells and affect their microenvironment. Cancer cells produce the excess of proangiogenic factors such as vascular endothelial growth factor (VEGF), bFGF (basic fibroblast growth factor), There are seven members of the VEGF family including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and placental growth factor. VEGF act specifically through tyrosine kinase receptors VEGFR-1, VEGFR-2 and VEGFR-3. The key molecule is VEGF-A (also referred to below as ‘VEGF’), induces angiogenesis by promoting proliferation, sprouting, migration and tube formation of endothelial cells. VEGF-A is one of the most potent facilitators of angiogenesis in cancers. VEGF binds to VEGFR-1 and activates the signalling through PI3K-Akt kinases and thus leads to increase in survival and migration. On the other hand, it induces the PLC activity by activation of c-src followed by interaction with VEGFR-2. It has been shown that VEGF expression is associated with metastatic capability in cancer. VEGF may induce disease progression by directly affecting the cell cycle components to accelerate cell proliferation. Metastasis is a very complex process, which occurs through a series of sequential steps including the invasion of adjacent tissue, intravasation, transport through the circulatory system, arrest and growth in a secondary site.
Clinical studies clearly show that tumor cells can undergo a period of dormancy followed by the rapid growth during the relapse. Homing of cancer cells to specific organs remains largely unknown. In carcinomas, the initial step of metastatic dissemination includes the detachment of epithelial cells from the extracellular matrix and disruption of actin cytoskeleton to achieve the round shape. The movement of migrating cells in tissue microenvironments requires proteolytic remodelling of the extracellular matrixes (ECM). The matrix metalloproteinases (MMPs) protein family members play an important role in ECM remodeling and cell invasion. The MMPs are zinc dependent endopeptidases that play multiple roles in biology of ECM, such as release of cryptic fragments and neo-epitopes from ECM macromolecules, release of growth factors and modification of the cell-ECM interface. Most MMPs are secreted proteins: however six of them are membrane proteins. The major function of MMPs is degradation of structural components of the ECM and directly or indirectly migration of cells. Degradation of extracellular matrix not only promotes migration, but also releases the essential growth factors from the matrix storage. Interestingly, MMPs contribute to the vessel remodeling by degradation of type I collagen, regulation of perivascular cells and VEGF processing. The changes of tissue architecture after release of MMPs are due to cleavage of E-cadherins and desmogleins. The expression and interaction of MMPs and TIMPs appear to be involved in invasion and metastases capacity of various cancers.
Several different types of cancer affect the world-wide population, for example those described hereinafter. Prostate cancer (PCa) is one of the most prevalent cancers and a leading cause of cancer related-death worldwide. Incidence of prostate cancer has significantly increased world-wide (Jemal A, Siegel R, Ward E, et al., Cancer statistics, 2006. CA: a cancer journal for clinicians 56: 106-130, 2006; Yin M, Bastacky S, Chandran U, Becich M J and Dhir R: Prevalence of incidental prostate cancer in the general population: a study of healthy organ donors; The Journal of urology 179: 892-895, discussion 895, 2008). Despite recent advances in early diagnosis and treatment, PCa remains the second most lethal cancer in men in the Western World (Jemal et al., ibid, Yin et al., ibid).
Initially, the majority of prostate cancers are responsive to androgen ablation therapy, but most of the tumors eventually will progress to the androgen-refractory state (Gronberg H: Prostate cancer epidemiology. Lancet 361: 859-864, 2003). Once prostate cancer becomes hormone-refractory, cancer cells may rapidly gain the ability to invade and to metastasize to lymph nodes and distant organs (Kalluri R: Basement membranes: structure, assembly and role in tumour angiogenesis. Nature reviews 3: 422-433, 2003).
Tumor metastases are the major cause of mortality in cancer patients. Approximately one-third of treated patients will relapse and no curative treatment currently exists for metastatic disease (Yin et al., ibid; Gronberg H, ibid; Albertsen P C, Hanley J A and Fine J: 20-year outcomes following conservative management of clinically localized prostate cancer. Jama 293: 2095-2101, 2005; Society AC: Cancer Facts & Figures 2008. Atlanta, Ga., American Cancer Society, 2008). The progression from hormone-dependent to hormone-refractory and metastatic prostate cancer is poorly understood. Given the high prevalence of the disease, the aging of the population, and the lack of effective treatment for cancer metastasis, there is an urgent need to discover and develop novel therapeutic approaches.
Primary PCa is treated with hormonal therapy, which is aimed to suppress the androgen production and block androgen receptor (AR)-mediated proliferation and survival pathways. In advanced PCa, androgen deprivation therapy (ADT) is the mainstay treatment. Surgical removal of the tumor and the use of hormone agonists or AR antagonists, such as flutamide, are the major types of ADT (DeMarzo A M, Nelson W G, Isaacs W B and Epstein J I: Pathological and molecular aspects of prostate cancer. Lancet 361: 955-964, 2003).
Docetaxel that targets the mitotic spindle and cell proliferation cycle is being used in advanced PCas. However, as a single agent, Docetaxel has modest activity. Current treatment of advanced metastatic cancer benefits from antiangiogenic drugs. Avastin™, a VEGF inhibitor, targets angiogenic pathways for the treatment of metastatic prostate cancer and has been tested in clinical trials (Di Lorenzo G, Figg W D, Fossa S D, et al.: Combination of Bevacizumab and Docetaxel in Docetaxel-Pre-treated Hormone-Refractory Prostate Cancer: A Phase 2 Study. European Urology 54: 1089-1096, 2008). When Avastin™ was used as a single agent or in combination with Docetaxel, the response rate was greatly improved. However, the side effects induced by Docetaxel and Avastin™ may be severe, as the individual drug's toxicities are now combined to cause multiple adverse effects, in particular myelosuppression and heart failure (Friberg L E, Henningsson A, Maas H, Nguyen L and Karlsson M O: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20: 4713-4721, 2002). In addition, the costs of these drugs are expensive.
Development of alternative treatments with minimal adverse effect and lower cost will therefore have great clinical and economical benefits.
The effective drug candidate for treatment of metastatic cancer should have the properties to target multiple cancer cell pathways including cell proliferation pathways, apoptosis pathways and angiogenesis signalling. High bioavailability for treatment of aggressive forms of cancer is also important.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
The compound etoposide is one that has been used in the treatment of various cancers. This compound contains a tetracyclic core, comprising a dioxolyl, tetrahydronaphthyl and tetrahydrofuranyl all fused in a series.
Heterocyclic compounds containing a pyrazinotetrahydro tetrahydroisoquinoline sub-unit, or variants thereof, are known for use as medicament, for example, as described in international patent application WO 98/16526 and journal article Crescendi, Orlando, 1997, Eur. J. Biochem., 247, 66-73. However, none of these documents relate to compounds in which such a sub-unit is substituted with an indolyl group.
Further, the following compound:
in which the hydrogen at the 9a position is in the S-configuration, and the 3-indolyl group at the 5-position is in the R-configuration (i.e. the above compound is of an absolute stereochemistry), has been isolated from botanical extracts in China. This compound and/or the extracts from which it may be isolated may have shown biological activity as a medicament. However, there is no disclosure regarding the potential synthetic preparation of such compounds, and moreover there is no disclosure of such a compound of a different relative and/or absolute stereochemistry for use as a medicament.